Abstract
Therapeutic resistance remains a major obstacle in treating many cancers, particularly in advanced stages. It is likely that cytotoxic lymphocytes (CTLs) have the potential to eliminate therapy-resistant cancer cells. However, their effectiveness may be limited either by the immunosuppressive tumor microenvironment, or by immune cell death induced by cytotoxic treatments. High-frequency low-dose (also known as metronomic) chemotherapy can help improve the activity of CTLs by providing sufficient stimulation for cytotoxic immune cells without excessive depletion. Additionally, therapy-induced removal of tumor cells that compete for shared nutrients may also facilitate tumor infiltration by CTLs, further improving prognosis. Metronomic chemotherapy can also decrease the number of immunosuppressive cells in the tumor microenvironment, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Immune checkpoint inhibition can further augment anti-tumor immune responses by maintaining T cells in an activated state. Combining immune checkpoint inhibition with metronomic administration of chemotherapeutic drugs may create a synergistic effect that augments anti-tumor immune responses and clears metabolic competition. This would allow immune-mediated elimination of therapy-resistant cancer cells, an effect that may be unattainable by using either therapeutic modality alone.
Highlights
The initial significant successes in curative chemotherapy occurred in the 1960s, when a combination of simultaneously administered chemotherapeutic drugs induced long-term remissions in children with acute lymphoblastic leukemia (ALL)
If chemotherapeutic treatment under the maximal tolerated dose (MTD) regimen is administered to such a tumor, does it result in the aforementioned selection for therapy-resistant clones via removal of sensitive cell clones, but it leaves behind a microenvironment that has been primed to favor the remaining cancer cells [4,7]
Cancer cells depend on supporting stroma to provide pro-angiogenic signaling that would allow the formation of blood vessels needed for recruiting nutrients and oxygen [27,39,40]
Summary
The initial significant successes in curative chemotherapy occurred in the 1960s, when a combination of simultaneously administered chemotherapeutic drugs induced long-term remissions in children with acute lymphoblastic leukemia (ALL). One of the mechanisms whereby many solid tumors engage and modify their microenvironments is through upregulation of the anaerobic metabolism of glucose (glycolysis) This natural adaptation to diminishing oxygen supply results from increased cell proliferation and greater inter-cellular competition for shared resources in the tumor microenvironment. If chemotherapeutic treatment under the MTD regimen is administered to such a tumor, does it result in the aforementioned selection for therapy-resistant clones via removal of sensitive cell clones, but it leaves behind a microenvironment that has been primed to favor the remaining cancer cells [4,7]. CCoommppaarriissoonn ooff tthhee eeffffeeccttss ooff mmaaxxiimmaall ttoolleerraatteedd ddoossee((MMTTDD))aannddmmeettrroonnoommiicccchheemmootthheerraappyy. RReemmoovviningg tthhee ssoouurrccee ooff aannggiiooggeenneessiiss ssttiimmuullaattoorrss ggiivveess aannggiiooggeenneessiiss iinnhhiibbiittoorrss aann ooppppoorrttuunniittyy ttoo ssiiggnnaall aanndd tteerrmmiinnaattee tthhee pprroocceessss ooff bblloooodd vveesssseell ffoorrmmaattiioonn
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